背景：研究已经表明组蛋白去乙酰化酶（HDACs）的表达与胃癌肿瘤微环境（TME）密切相关。然而，单个分子或几个分子的表达不能准确地反映胃癌的TME特征或指导免疫治疗。方法：我们根据HDACs的表达水平构建了一个HDAC评分（HDS）。利用单细胞转录组分析了在高HDS和低HDS患者之间免疫浸润差异的潜在因素。体外和体内实验证实了将冷性肿瘤转化为热性肿瘤以指导免疫治疗的策略。结果：根据HDACs的表达特征，我们构建了一个HDS模型来表征TME。我们发现高HDS患者有更强的免疫原性，并且比低分数患者更能从免疫治疗中受益。HDS与联合阳性评分（CPS）结合预测免疫治疗疗效的AUC值高达0.96。通过单细胞和成对块转录组测序分析，我们发现低HDS组中CD4+ T细胞、CD8+ T细胞和NK细胞的浸润水平显著降低，可能是由MYH11+成纤维细胞、CD234+内皮细胞和CCL17+ pDCs通过MIF信号通路诱导的。抑制MIF信号通路确认可以增强免疫浸润。此外，我们的分析还发现GPX4抑制剂可能对低HDS患者有效。GPX4敲除显著抑制PD-L1的表达，并促进CD8+ T细胞的浸润和激活。结论：我们基于胃癌的HDAC表达特征构建了一个HDS模型。该模型用于评估TME特征和预测免疫治疗疗效。抑制TME中的MIF信号通路和肿瘤细胞中的GPX4表达可能是胃癌冷性肿瘤协同免疫治疗的重要策略。© 作者（们）。

Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.© The author(s).